ALCOHOLIC LIVER DISEASE (ALD) Nayan Patel, DO Transplant Hepatology/GI Banner Advanced Liver Disease and Transplant Center

Objectives Spectrum of alcoholic liver disease Focus on Alcoholic Hepatitis (AH) Pathophysiology and role of inflammation in AH Scoring systems to assess severity Treatment algorithm Role of corticosteroids and pentoxifylline (PTX)

Epidemiology In the U.S., approximately 67% of people drink alcohol Majority drink small or moderate amounts No evidence of clinical disease Alcohol dependence - drink excessively, develop physical tolerance and withdrawal (3.8%) Alcohol abusers and problem drinkers (4.5%) those who engage in harmful use of alcohol, defined by the development of negative social and health consequences of drinking (e.g., repeated absences or poor work performance, recurrent legal problems, neglect of family or children, organ damage, accidental injury, or death)

Epidemiology Alcoholic cirrhosis 8 th leading cause of death in US 40% of deaths from cirrhosis 30% of deaths from HCC

ALD Development of liver injury the dose, duration, drinking patterns, sex, ethnicity; associated risk factors including obesity, iron overload, concomitant infection with viral hepatitis, and genetic factors The amount of alcohol ingested (independent of the form in which it is ingested) is the most important risk factor for the development of ALD Risk of cirrhosis Men >60-80grams/day Women >20grams/day One drink (12 oz beer, 4 oz wine, 1-1.5 oz spirit) =10-12 grams

ALD

Ethanol Metabolism Alcohol dehydrogenase (ADH), Cytochrome P450 2E1 (CYP2E1), Catalase (less important) ADH is the primary enzyme system responsible for metabolism of ethanol at low concentrations, CYP2E1 contributes at higher concentrations of ethanol and is induced by exposure to ethanol Influences drug metabolism (acetaminophen/isoniazid toxicity)

Liver Injury Acetaldehyde: highly reactive and potentially toxic compound that is responsible for many of the systemic toxic effects of alcohol, such as nausea, headaches, and flushing Increased levels in blood and liver tissue in alcoholic liver disease

Effect of increased acetaldehyde (triggered by heavy drinking): production of protein adducts and immune response leading to liver damage. Activation of stellate cells and fibroblasts, leading to liver fibrosis.

Liver Injury Oxidant Stress Induction of CYP2E1 by alcohol intake stimulates the formation of reactive oxygen species (ROS) during ethanol oxidation Overproduction of ROS, or inadequate antioxidant defenses (e.g., low levels of vitamins, selenium, mitochondrial glutathione),can lead to liver injury Oxidant stress also leads to stellate cell activation causing steatosis and fibrosis

Liver Injury - Endotoxins Bacterial endotoxin is a toxic lipopolysaccharide (LPS) present in the cell wall of some intestinal bacteria When bacteria die, the endotoxin is released and enters the portal and systemic circulation Excess EtOH leads to increased intestinal permeability (disruption of the mucosal barrier) and increased endotoxemia Ultimately leads to upregulation of proinflammatory cytokines (notably TNF α)

Alcoholic Hepatitis Acute hepatic inflammation associated with significant morbidity and mortality that occurs in a subset of patients who consume excessive amounts of alcohol Clinical syndrome of jaundice and liver failure that generally occurs after decades of heavy alcohol use (mean intake, approximately 100 g per day) Can occur several weeks after alcohol abstinence Usually age 40-60, Female sex an independent risk factor for AH Cardinal sign is rapid onset of jaundice

Alcoholic Hepatitis Severe cases, mortality 30-50% Spectrum from mild to severe Often times on background of cirrhosis

Presentation Fever, tachycardia Encephalopathy Physical Exam: jaundice, enlarged and tender liver, hepatic bruit, parotid enlargement, Dupuytren contracture, spider nevi, ascites Labs: AST(2x) > ALT (usually <300 IU/ml), Tbili > 5, Leukocytosis, thrombocytopenia, elevated INR, Hypokalemia, hypomagnesemia, hyperuricemia, elevated ferritin hypertriglyceridemia, low zinc level, hypoalbuminemia, elevated MCV. Elevated Cr (ominous)

Differential Diagnosis Decompensated cirrhosis, Acute or chronic viral hepatitis, Drug-induced liver injury, Fulminant Wilson s disease, Autoimmune liver disease, Alpha-1 antitrypsin deficiency, Pyogenic hepatic abscess, Ascending cholangitis, Decompensation associated with hepatocellular carcinoma

Work-up Screen for bacterial infections Blood culture, CXR, spontaneous bacterial peritonitis, and urinary tract infection Hepatic ultrasonography hepatic abscess, hepatocellular carcinoma, and biliary obstruction, each of which may mimic alcoholic hepatitis.

Assessing Disease Severity

Maddrey s Discriminant Function DF: 4.6 (PT-control)+TB DF >32 indicates a poor prognosis Mortality up to 44-62% Limitations Not used to guide therapy. DF < 32 are still at risk for mortality Results can vary among laboratory

MELD Score MELD Score = 3.8 * log e (bilirubin in mg/dl) 11.2 * log e (INR) 9.6 * log e (creatinine mg/dl) 6.4 MELD 21, estimated 90 day mortality of 20% Increase in MELD 2 in first week has been shown to predict in hospital mortality

Glasgow Alcoholic Hepatitis Score age, leukocyte count, serum urea level, PT ratio (ratio of patient-to-control PT), and serum bilirubin level A score > 8 predicts poor prognosis Score > 9 78% 28- day survival with corticosteroids vs. 52% without 59% vs. 38%, 84 day survival Rarely used clinically

ABIC most recent scoring system, includes age, serum bilirubin, INR, and serum creatinine. It stratifies risk of mortality from AH as low (score < 6.71), intermediate (score:6.71-8.99), and high (score 9.0), with 90 d mortality at 0%, 30%, and 75%, respectively (P < 0.0001) Rarely used clinically & Not validated externally

Treatment - Abstinence Current therapy focuses on supportive care & complete EtOH abstinence AH may persist for months after cessation, and may worsen during the first weeks of abstinence. Inpatient: measures for decompensated cirrhosis in many cases Thiamine, MVI, folate, pyridoxine Watch for DTs and EtOH withdrawal

Treatment - Nutrition Protein calorie malnutrition Vitamin deficiencies Risk of death correlated with malnutrition AASLD: 1.2 1.5 g/kg protein and 35-40 kcal/kg total calories

Treatment - Nutrition Randomized, controlled clinical trial compared enteral tube feeding (2000 kcal per day) with prednisolone therapy (40 mg of prednisolone per day) for 28 days in 71 patients with severe alcoholic hepatitis. The survival rate in the two groups was similar at 28 days Overall lower mortality in nutrition group at 1 year (p=ns) Nutritional support may be as effective as corticosteroids in some patients

Treatment - Corticosteroids Rationale is to decrease the immune and proinflammatory cytokine response. There have been 13 randomized, controlled trials evaluating corticosteroids in alcoholic hepatitis Inconsistent results with 5 showing reduction in mortality, and the remainder showing no benefit

-significant increase in short-term survival among treated patients compared to control patients: 84.6% versus 65%. -30% relative risk reduction, and translates into a number needed to treat of 5,

Treatment - Corticosteroids Active infections, gastrointestinal bleeding, pancreatitis, renal failure, and non-compliance are excluded, because corticosteroids treatment may adversely affect these conditions Prednisolone 40mg/d for 4 weeks then tapered over 2-4 weeks Active form of prednisone, and not metabolized by liver Still, 40% of patients unresponsive

Lille Score Predicts 6 months survival in patients treated with corticosteroids based on pretreatment data plus the response of serum levels of bilirubin to a 7-day course of corticosteroid therapy A score < 0.45 predicts 15% mortality, whereas a score 0.45 predicts 75% mortality (P < 0.0001). Alternative therapies should be considered when the score is 0.45 at day 7 of corticosteroid therapy

Treatment TNF α inhibitors Pentoxifylline (PTX), a nonselective phosphodiesterase inhibitor that inhibits TNF synthesis One prospective, randomized, double blind clinical trial in 101 patients who had severe alcoholic hepatitis (mdf score 32) PTX 400mg PO TID vs placebo In-hospital mortality lower (24.5% vs 46.1%)

Treatment TNF α inhibitors The survival benefit of PTX seemed to result from a significant decrease in the risk of death from hepatorenal syndrome PTX group 6 of 12 deaths (50%) Placebo group 22 of 24 deaths (92%) The mechanism by which PTX decreased the development of hepatorenal syndrome is not clearly explained in this study Most authorities advocate PTX for patients with contraindications to using corticosteroids

Treatment TNF α inhibitors Infliximab (chimeric human/mouse TNF α antibody) infusion - Trials with no benefit, one with no survival advantage - Another with infliximab + prednisolone vs prednisolone alone stopped prematurely because of higher death rate related to severe infections Etanercept (p75-soluble TNF receptor:fc fusion protein) RCT, mod-sev AH Compared with placebo, etanercept was associated with significantly higher mortality (mainly due to infections) after six months (58 versus 23 percent)

Management Algorithm

-1103 patients with severe acute alcoholic hepatitis DF >32 -randomized to placebo, Prednisolone, PTX, or combination -28 day mortality -Prednisolone vs. placebo (14% vs 17%, ns) -PTX vs. placebo (19% vs 17%) -study limitations

References Akrividias et al. Pentoxifylline improves short term survival in severe acute alcoholic hepatitis: a double blind placebo-controlled trial. Gastroenterology 2000;119:1637-1648. Ceccanti et al. Acute alcoholic hepatitis. J Clin Gastroenterol 2006;40(9):833-841. Chayanupatkul M et al. Alcoholic hepatitis: a comprehensive review of pathogenesis and treatment. World J Gastroenterol. 2014;28;20(20):6279-86. Haber et al. Pathogenesis and management of alcoholic hepatitis. Journal of Gastroenterology and Hepatology 2003;18:1332-1344. Lucey MR et al. Alcoholic Hepatitis. NEJM 2009;360(26):2758-69. O Shea RS. Alcoholic Liver Disease. AASLD guidelines. Hepatology 2010 Singal AK et al. Alcoholic Hepatitis: Current Challenges and Future Directions. Clinical Gastroenterology and Hepatology 2014;12:555 564. Suk KT et al. Alcoholic liver disease: Treatment. World J Gastroenterol 2014 20(36): 12934-12944